The ventral, medial prefrontal cortex and cingulate cortex, the major white matter pathways that connect them (and their links to the basal ganglia) are central parts of the reward/motivation circuit. Dysfunction in these areas is associated with several psychiatric diseases including depression. Fibers from these cortical areas are captured at two surgical targets for treatment resistant depression (anterior cingulotomy and deep brain stimulation of the subgenual cingulate). The goal of this application is to gain insight into the anatomical substrates that underlie human functional connectivity profiles and changes in disease derived from imaging studies. Cortex and basal ganglia are generally organized in parallel functional circuits, yet emerging data indicate that specific subregions also serve as connectional nodes that integrate information processing across functional systems. Our work has focused on how prefrontal cortical regions are anatomically linked through the basal ganglia, to integrate across reward/motivation and cognitive domains. We have recently expanded these studies to examine cortico-cortical connections, particularly, the white matter pathways that connect them. By combining anatomical tracing and diffusion magnetic resonance imaging we are exploring the ability of imaging to replicate fiber pathways. The aim here is to build on our previous findings combining non-human primate anatomical tracing, non-human primate diffusion magnetic resonance imaging, and human dMRI to identify cortical and basal ganglia areas that anatomically link areas of prefrontal cortex and cingulate cortex. Data will be used to determine the pathways/structures involved at the cingulotomy and subgenual DBS targets. Aim 1 uses conventional tracing experiments to determine how cingulate and prefrontal cortical terminals and pathways interface. Aim 2 will determine their pathways through the cingulum, uncinate fasciculus, and corpus callosum, and the ability for diffusion imaging tractography to replicate these connections. Aim 3 will use the results from Aim 2 to evaluate and segment the cingulum and uncinate fasciculus, and the corpus callosum in healthy human subjects and delineate which connections are likely to pass through the surgical targets, the dorsal anterior cingulate (cingulotomy) and subgenual anterior cingulate (deep brain stimulation).